Compounds of the formula I belong to the series of water-soluble aminoacyl forskolin derivatives which display potent pharmacological properties. They are the subject of different patent applications and publications viz. EP application No. 0222413, Synthesis 711, 1989 Indian Pat. Appl. No. 164675, Ger. Pat. appln. No. 3623300-5. J.P. Appln. No. 159638, Ind. Pat. Appln. No. 238/BOM/87, Ger. Pat. Appl. No. 3737353.6, Mol. Pharmacol., 32, 133 (1987). Processes for their preparation have also been described. The different sequence through which compounds of the formula I have been prepared can be summarised as shown in FIG. 1:
Inventive steps of the current invention:
In view of the high importance of compounds of the formula I for use in cardiovascular drug therapy, different inventive steps have been introduced in a process for their preparation using the 1,9-O-isopropylidene protecting group in forskolin.
1st Inventive Step: The 1,9-O-isopropylidene derivative of forskolin has surprisingly been now found to be formed in almost quantitative yield (96-97%) through reaction of forskolin with acetone in the presence of hydrogen chloride, in contrast with the earlier process using anhydrous aluminum chloride/ether/acetone (cf. Syn. Synthesis 711-713, 1989). PA1 2nd Inventive Step: The treatment of the 1,9-O-isopropylidene derivative of 7-deacetylforskolin with .beta.-halopropionylhalide, preferably .beta.-chloropropionylchloride and triethylamine in toluene has surprisingly been now found to result in the formation of the novel 1,9-O-isopropylidene derivative of 7.beta.-acryloyloxyforskolin in &gt;90% yield. PA1 3rd Inventive Step: Treatment of the 1,9-O-isopropylidene derivative of 7.beta.-acryloyloxyforskolin with aqueous sodium hydroxide in acetonitrile has surprisingly been now found to result in the formation of the novel 1,9-O-isopropylidene derivative of 6.beta.-acryloyloxy-7-deacetylforskolin in &gt;90% yields.
More specifically the invention describes a process for the preparation of compounds of the formula I according to the sequence shown in FIG. 2.